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A heme (American English
American English

PhonologyIn many ways, compared to English language in England, North American English is conservative in its phonology. Some distinctive accents can be found on the East Coast of the United States , partly because these areas were in contact with England, and imitated prestigious varieties of English English at a time when those varieties we...
) or haem (British English
British English

British English or UK English is the broad term used to distinguish the forms of the English language used in the United Kingdom from forms used elsewhere....
) is a prosthetic group
Prosthetic group

A prosthetic group is a non-protein component of a conjugated protein that is required for the protein's biological activity. The prosthetic group may be organic compound or inorganic ....
 that consists of an iron
Iron

Iron is a chemical element with the symbol Fe and atomic number 26. Iron is a Group 8 element and period 4 element. Iron is lustrous and silvery in color....
 atom contained in the center of a large heterocyclic organic ring called a porphyrin
Porphyrin

Porphyrins are a group of chemical compounds of which many occur in nature, such as in green leaves and red blood cells, and in bio-inspired synthetic catalysts and devices....
. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloprotein
Metalloprotein

Metalloprotein is a generic term for a protein that contains a metal ion Cofactor . Metalloproteins have many different functions in cell , such as enzymes, transport and storage proteins, and signal transduction proteins....
s have heme as their prosthetic subunit; these are known as hemoprotein
Hemoprotein

A hemeprotein , or heme protein, is a metalloprotein containing a heme prosthetic group, either Covalent bond or noncovalently chemical bond to the protein itself....
s.

e are several biologically important kinds of heme:

The most common type is heme B
Heme b

Heme B is the most abundant heme; both hemoglobin and myoglobin are examples of oxygen transport proteins that contain heme B and the peroxidase family of enzymes also contain heme B....
; other important types include heme A
Heme a

Heme A differs from heme B in that a methyl side chain at ring position 8 is oxidized to a formyl group and a farnesyl group, an isoprene chain, has been attached to the vinyl side chain at ring position 2 of the iron tetrapyrrole heme....
 and heme C
Heme c

Heme C differs from heme B in that the two vinyl side chains are covalently bound to the apoprotein itself through thioether linkages.In addition to these covalent bonds, the heme iron is also usually coordinated to two side chains of amino acids, making the iron hexacoordinate....
.






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Haem B 3d Vdw
A heme (American English
American English

PhonologyIn many ways, compared to English language in England, North American English is conservative in its phonology. Some distinctive accents can be found on the East Coast of the United States , partly because these areas were in contact with England, and imitated prestigious varieties of English English at a time when those varieties we...
) or haem (British English
British English

British English or UK English is the broad term used to distinguish the forms of the English language used in the United Kingdom from forms used elsewhere....
) is a prosthetic group
Prosthetic group

A prosthetic group is a non-protein component of a conjugated protein that is required for the protein's biological activity. The prosthetic group may be organic compound or inorganic ....
 that consists of an iron
Iron

Iron is a chemical element with the symbol Fe and atomic number 26. Iron is a Group 8 element and period 4 element. Iron is lustrous and silvery in color....
 atom contained in the center of a large heterocyclic organic ring called a porphyrin
Porphyrin

Porphyrins are a group of chemical compounds of which many occur in nature, such as in green leaves and red blood cells, and in bio-inspired synthetic catalysts and devices....
. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloprotein
Metalloprotein

Metalloprotein is a generic term for a protein that contains a metal ion Cofactor . Metalloproteins have many different functions in cell , such as enzymes, transport and storage proteins, and signal transduction proteins....
s have heme as their prosthetic subunit; these are known as hemoprotein
Hemoprotein

A hemeprotein , or heme protein, is a metalloprotein containing a heme prosthetic group, either Covalent bond or noncovalently chemical bond to the protein itself....
s.

Types


Major hemes

There are several biologically important kinds of heme:

  Heme a
Heme a

Heme A differs from heme B in that a methyl side chain at ring position 8 is oxidized to a formyl group and a farnesyl group, an isoprene chain, has been attached to the vinyl side chain at ring position 2 of the iron tetrapyrrole heme....
 Heme b
Heme b

Heme B is the most abundant heme; both hemoglobin and myoglobin are examples of oxygen transport proteins that contain heme B and the peroxidase family of enzymes also contain heme B....
 Heme c
Heme c

Heme C differs from heme B in that the two vinyl side chains are covalently bound to the apoprotein itself through thioether linkages.In addition to these covalent bonds, the heme iron is also usually coordinated to two side chains of amino acids, making the iron hexacoordinate....
 Heme o
Heme o

Heme O differs from the closely related heme A by having a methyl group at ring position 8 instead of the formyl group, the isoprenoid chain at position 2 is the same....
PubChem number
Chemical formula C49H56O6N4Fe C34H32O4N4Fe C34H36O4N4S2Fe C49H58O5N4Fe
Functional group at C3 Hydroxyfarnesyl -CH=CH2 -CH-(CH3)-SH Hydroxyfarnesyl
Functional group at C8 -CH=CH2 -CH=CH2 -CH-(CH3)-SH -CH=CH2
Functional group at C18 -CH=O -CH3 -CH3 -CH3
Heme
Heme A
The most common type is heme B
Heme b

Heme B is the most abundant heme; both hemoglobin and myoglobin are examples of oxygen transport proteins that contain heme B and the peroxidase family of enzymes also contain heme B....
; other important types include heme A
Heme a

Heme A differs from heme B in that a methyl side chain at ring position 8 is oxidized to a formyl group and a farnesyl group, an isoprene chain, has been attached to the vinyl side chain at ring position 2 of the iron tetrapyrrole heme....
 and heme C
Heme c

Heme C differs from heme B in that the two vinyl side chains are covalently bound to the apoprotein itself through thioether linkages.In addition to these covalent bonds, the heme iron is also usually coordinated to two side chains of amino acids, making the iron hexacoordinate....
. Isolated hemes are commonly designated by capital letters while hemes bound to proteins are designated by lower case letters. Cytochrome a refers to the heme A in specific combination with membrane protein forming a portion of cytochrome c oxidase
Cytochrome c oxidase

The enzyme cytochrome c oxidase or Complex IV is a large transmembrane protein complex found in bacteria and the mitochondrion.It is the last enzyme in the respiratory electron transport chain of mitochondria located in the mitochondrial membrane....
.

Other hemes

  • Heme L is the derivative of heme B which is covalently attached to the protein of lactoperoxidase, eosinophil peroxidase and thyroid peroxidase. The addition of peroxide with the glutamyl-375 and aspartyl-225 of lactoperoxidase forms ester bonds between these amino acid residues and the heme 1- and 5-methyl groups, respectively. Similar ester bonds with these two methyl groups are thought to form in eosinophil and thyroid peroxidases. Heme L is one important characteristic of animal peroxidases; plant peroxidases incorporate heme B. Lactoperoxidase and eosinophil peroxidase are protective enzymes responsible for the destruction of invading bacteria and virus. Thyroid peroxidase is the enzyme catalyzing the biosynthesis of the important thyroid hormones. Because lactoperoxidase destroys invading organisms in the lungs and excrement, it is thought to be an important protective enzyme.


  • Heme M is the derivative of heme B covalently bound at the active site of myeloperoxidase
    Myeloperoxidase

    Myeloperoxidase is a peroxidase enzyme most abundantly present in neutrophil granulocytes . It is a lysosome protein stored in azurophilic granules of the neutrophil....
    . Heme M also contains the two ester bonds at the heme 1- and 5-methyls, much as the other mammalian peroxidases. In addition, a unique sulfonium
    Sulfonium

    A sulfonium ion, also known as sulphonium ion and sulfanium ion, is a positively charged sulfur ion carrying three alkyl functional group as Substitution ....
     ion linkage between the sulfur of a methionyl aminoacid residue and the heme 2-vinyl group is formed, giving this enzyme the unique capability of easily oxidizing chloride
    Chloride

    The chloride ion is formed when the chemical element chlorine picks up one electron to form an anion Cl−....
     and bromide
    Bromide

    A bromide ion is a bromine atom with electric charge of -1.Compounds with bromine in formal oxidation state -1 are called bromides, and each individual chemical in this class can be called a bromide, as well....
     ions. Myeloperoxidase is present in mammalian neutrophils and is responsible for the destruction of invading bacteria and virus. It also synthesizes hypobromite
    Hypobromite

    The hypobromite ion is BrO-. Bromine is in oxidation state +1....
     by "mistake" which is a known mutagenic compound.


  • Heme D is another derivative of heme B, but in which the propionic acid side chain at the carbon of position 6, ring III is bound to this carbon both via the usual C-C bond but also by the carboxyl oxygen, giving heme D a fifth ring and a lactone. Ring III is also hydroxylated at position 5, in a conformation trans to the new lactone group. Heme D is the site for oxygen reduction to water of many types of bacteria at low oxygen tension.


  • Heme S is related to heme B by the having a formyl group at position 2 in place of the 2-vinyl group. Heme S is found in the hemoglobin of marine worms. The correct structures of heme B and heme S were first elucidated by German chemist Hans Fischer
    Hans Fischer

    Hans Fischer was a Germany organic chemistry and the recipient of the 1930 Nobel Prize for Chemistry....
    .


The names of cytochrome
Cytochrome

Cytochromes are, in general, membrane-bound hemoproteins that contain heme groups and carry out electron transport.They are found either as subunitss or as subunits of bigger enzymatic complexes that catalyze redox reactions....
s typically (but not always) reflect the kinds of hemes they contain: cytochrome a contains heme A, cytochrome c contains heme C, etc.

Function

Hemoproteins have diverse biological functions including the transportation of diatomic gases, chemical catalysis
Catalysis

Catalysis is the process in which the reaction rate of a chemical reaction is either increased or decreased by means of a chemical substance known as a catalyst....
, diatomic gas detection, and electron transfer. The heme iron serves as a source or sink of electrons during electron transfer or redox chemistry. In peroxidase
Peroxidase

Peroxidases are a large family of enzymes. A majority of peroxidase protein sequences can be found in the PeroxiBase database. Peroxidases typically catalyze a reaction of the form:...
 reactions, the porphyrin
Porphyrin

Porphyrins are a group of chemical compounds of which many occur in nature, such as in green leaves and red blood cells, and in bio-inspired synthetic catalysts and devices....
 molecule also serves as an electron source. In the transportation or detection of diatomic gases, the gas binds to the heme iron. During the detection of diatomic gases, the binding of the gas ligand
Ligand

In chemistry, a ligand is either an atom, ion, or molecule that bonds to a central metal, generally involving formal donation of one or more of its electrons....
 to the heme iron induces conformational changes in the surrounding protein.

It has been speculated that the original evolutionary function of hemoproteins was electron transfer in primitive sulfur-based photosynthesis
Photosynthesis

File:Seawifs global biosphere.jpgPhotosynthesis is a metabolic pathway that converts carbon dioxide into organic compounds, especially sugars, using the energy from sunlight....
 pathways in ancestral cyanobacteria
Cyanobacteria

Cyanobacteria, also known as blue-green algae, blue-green bacteria or Cyanophyta, is a phylum of bacteria that obtain their energy through photosynthesis....
 before the appearance of molecular oxygen.

Hemoproteins achieve their remarkable functional diversity by modifying the environment of the heme macrocycle within the protein matrix. For example, the ability of hemoglobin
Hemoglobin

Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of vertebrates, and the tissues of some invertebrates....
 to effectively deliver oxygen to tissues is due to specific amino acid residues located near the heme molecule. Hemoglobin binds oxygen in the pulmonary
Lung

The lung is the essential respiration organ in air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located in the chest on either side of the heart....
 vasculature, where the pH
PH

pH is a measure of the Acid or Base of a solution. It is defined as the cologarithm of the Activity of dissolved hydrogen ions . Hydrogen ion activity coefficients cannot be measured experimentally, so they are based on theoretical calculations....
 is high and the pCO2 is low, and releases it in the tissues, where the situations are reversed. This phenomenon is known as the Bohr effect
Bohr effect

Bohr effect is a property of hemoglobin first described in 1904 by the Danish physiologist Christian Bohr , which states that in the presence of carbon dioxide, the oxygen affinity for dissociation of respiratory pigments, such as hemoglobin, decreases; because of the Bohr effect, an increase in blood carbon dioxide level or a decrease in p...
. The molecular mechanism behind this effect is the steric organization of the globin chain; a histidine
Histidine

Histidine is one of the 20 standard amino acids present in proteins. In the nutritional sense, in humans, histidine is considered an essential amino acid, but only in children....
 residue, located adjacent to the heme group, becomes positively charged under acid circumstances, sterically releasing oxygen from the heme group.

Synthesis

Details of heme synthesis can be found in the article on porphyrin
Porphyrin

Porphyrins are a group of chemical compounds of which many occur in nature, such as in green leaves and red blood cells, and in bio-inspired synthetic catalysts and devices....
.

Heme Synthesis
The enzymatic process that produces heme is properly called porphyrin
Porphyrin

Porphyrins are a group of chemical compounds of which many occur in nature, such as in green leaves and red blood cells, and in bio-inspired synthetic catalysts and devices....
 synthesis, as all the intermediates are tetrapyrrole
Pyrrole

Pyrrole, or pyrrol, is a heterocyclic aromatic organic compound, a five-membered ring with the chemical formula carbon4hydrogen4nitrogenH....
s that are chemically classified are porphyrins. The process is highly conserved across biology. In humans, this pathway serves almost exclusively to form heme. In other species, it also produces similar substances such as cobalamin
Cobalamin

Cobalamin may refer to several substances depending on the upper axial ligand of the cobalt ion. These are:*Cyanocobalamin , which is not found in nature....
 (vitamin B12
Vitamin B12

Vitamin B12 is a water soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood....
).

The pathway is initiated by the synthesis of D-Aminolevulinic acid
D-Aminolevulinic acid

D-Aminolevulinic acid is the first compound in the porphyrin synthesis pathway, the pathway that leads to hemoglobin in mammals and chlorophyll in plants....
 (dALA or dALA) from the amino acid
Amino acid

In chemistry, an amino acid is a molecule containing both amine and carboxyl functional groups. These molecules are particularly important in biochemistry, where this term refers to alpha-amino acids with the general formula H2NCHRCOOH, where R is an organic substituent....
 glycine
Glycine

Glycine is the organic compound with the chemical formula NH2CH2COOH. It is the smallest of the 20 amino acids commonly found in proteins, coded by codons GGU, GGC, GGA and GGG....
 and succinyl-CoA
Succinyl-CoA

Succinyl-Coenzyme A, generally abbreviated as Succinyl-CoA or SucCoA is a combination of succinic acid and coenzyme A....
 from the citric acid cycle
Citric acid cycle

The citric acid cycle ? also known as the tricarboxylic acid cycle ; the Krebs cycle; or, more rarely, the Szent-Gy?rgyi-Krebs cycle) ? is a series of enzyme-catalysed chemical reactions of central importance in all living cell s that use oxygen as part of cellular respiration....
 (Krebs cycle). The rate-limiting enzyme responsible for this reaction, ALA synthase, is strictly regulated by intracellular iron
Iron

Iron is a chemical element with the symbol Fe and atomic number 26. Iron is a Group 8 element and period 4 element. Iron is lustrous and silvery in color....
 levels and heme concentration. A low-iron level, e.g., in iron deficiency
Iron deficiency

Iron deficiency may refer to:*Iron deficiency *Iron deficiency ...
, leads to decreased porphyrin synthesis, which prevents accumulation of the toxic intermediates. This mechanism is of therapeutic importance: infusion of heme arginate or hematin can abort attacks of porphyria
Porphyria

Porphyrias are a group of inherited or acquired disorders of certain enzymes in the heme biosynthetic pathway . They are broadly classified as acute porphyrias and cutaneous porphyrias, based on the site of the overproduction and accumulation of the porphyrins ....
 in patients with an inborn error of metabolism
Inborn error of metabolism

Inborn errors of metabolism comprise a large class of genetics diseases involving disorders of metabolism. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances into others ....
 of this process, by reducing transcription of ALA synthase.

The organs mainly involved in heme synthesis are the liver
Liver

The liver is a vital organ present in vertebrates and some other animals; it has a wide range of functions, a few of which are detoxification, protein synthesis, and production of biochemicals necessary for digestion....
 and the bone marrow
Bone marrow

Bone marrow is the flexible biological tissue found in the hollow interior of bones. In adults, marrow in large bones produces new blood cells....
, although every cell requires heme to function properly. Heme is seen as an intermediate molecule in catabolism of haemoglobin in the process of bilirubin metabolism.

Degradation

In the first step, heme is converted to biliverdin
Biliverdin

Biliverdin is a green pigment formed as a byproduct of heme breakdown. It consists of four linearly-connected pyrrole rings . Biliverdin is formed when a heme prosthetic group is cleaved at its a-methine bridge....
 by the enzyme heme oxygenase
Heme oxygenase

Heme oxygenase is an enzyme that catalyst the degradation of heme. This produces biliverdin, iron, and carbon monoxide....
 (HOXG). NADPH is used as the reducing agent, molecular oxygen enters the reaction, carbon monoxide is produced and the iron is released from the molecule as the ferric ion (Fe3+). HOXG heme --------------> biliverdin + Fe3+ / \ H+ + NADPHNADP+ O2 CO

In the second reaction, biliverdin is converted to bilirubin by biliverdin reductase
Biliverdin reductase

Biliverdin reductase is an enzyme that converts biliverdin to bilirubin, converting a double-bond between the second and third pyrrole ring into a single-bond....
 (BVR):

BVR biliverdin -----------> bilirubin / \ H+ + NADPH NADP+

Bilirubin is transported into the liver bound to a protein (serum albumin
Serum albumin

Serum albumin, often referred to simply as albumin, is the most abundant plasma protein in humans and other mammals. Albumin is essential for maintaining the osmotic pressure needed for proper distribution of body fluids between intravascular compartments and body tissues....
), where it is conjugated with glucuronic acid
Glucuronic acid

Glucuronic acid is a carboxylic acid. Its structure is similar to that of glucose. However, glucuronic acid's sixth carbon is oxidized to a carboxylic acid....
 to become more water soluble. The reaction is catalyzed by the enzyme UDP-glucuronide transferase (UDPGUTF). UDPGUTF bilirubin + 2 UDP-glucuronate ------------> bilirubin diglucuronide \ 2 UMP + 2 Pi

This form of bilirubin is excreted from the liver in bile
Bile

Bile or gall is a bitter yellow or green fluid secreted by hepatocytes from the liver of most vertebrates. In many species, bile is stored in the gallbladder between meals and upon eating is discharged into the duodenum where the bile aids the process of digestion of lipids....
. The intestinal bacteria deconjugate bilirubin diglucuronide
Bilirubin diglucuronide

Bilirubin diglucuronide is a conjugated form of bilirubin.See also* uridine triphosphate...
 and convert bilirubin to urobilinogen
Urobilinogen

Urobilinogen is a colourless product of bilirubin reduction. It is formed in the intestines by bacterial action. Some urobilinogen is reabsorbed, taken up into the circulation and excreted by the kidney....
s. Some urobilinogen is absorbed by intestinal cells and transported into the kidneys and excreted with urine. The remainder travels down the digestive tract and is excreted as stercobilinogen
Stercobilinogen

Stercobilinogen is a precursor of stercobilin.Bilirubin is pigment which results from the breakdown of the heme moiety of hemoglobin. The liver conjugates bilirubin, making it water soluble and the conjugated form is excreted in urine , giving urine its colour....
, which is responsible for the color of feces
Feces

Feces, faeces, or f?ces is a waste product from an animal's gastrointestinal tract expelled through the anus during defecation....
.

Genes

The following genes are part of the chemical pathway for making heme:

  • ALAD: aminolevulinic acid, delta-, dehydratase
    Dehydratase

    Dehydratase is an enzyme that catalyzes the removal of oxygen and hydrogen from organic compounds in the form of water. This process is also known as dehydration....
  • ALAS1
    ALAS1

    Delta-aminolevulinate synthase 1 also known as ALAS1 is a protein which in humans is encoded by the ALAS1 gene. ALAS1 is an aminolevulinic acid synthase....
    : aminolevulinate, delta-, synthase 1
  • ALAS2
    ALAS2

    Delta-aminolevulinate synthase 2 also known as ALAS2 is a protein which in humans is encoded by the ALAS2 gene. ALAS2 is an aminolevulinic acid synthase....
    : aminolevulinate, delta-, synthase 2 (sideroblastic/hypochromic anemia)
  • CPOX
    CPOX

    CPOX may refer to:*Coproporphyrinogen III oxidase*Catalytic partial oxidation...
    : coproporphyrinogen oxidase
    Oxidase

    An oxidase is any enzyme that catalyst an redox reaction involving molecular oxygen as the electron acceptor. In these reactions, oxygen is reduced to water or hydrogen peroxide ....
  • FECH: ferrochelatase
    Ferrochelatase

    Ferrochelatase is an enzyme that catalyses the terminal step in the biosynthesis of heme, converting protoporphyrin IX into heme. It catalyses reaction: protoporphyrin + Fe++ ? protoheme + 2 H+....
     (protoporphyria)
  • HMBS: hydroxymethylbilane synthase
    Synthase

    In biochemistry, a synthase is an enzyme which catalyzes a synthesis process.Following the EC number classification, they belong to the group of ligases, with lyases catalysing the reverse reaction....
  • PPOX
    PPOX

    Protoporphyrinogen oxidase, also known as PPOX, is a human gene.PPOX is a human gene that produces an enzyme called protoporphyrinogen oxidase....
    : protoporphyrinogen oxidase
    Oxidase

    An oxidase is any enzyme that catalyst an redox reaction involving molecular oxygen as the electron acceptor. In these reactions, oxygen is reduced to water or hydrogen peroxide ....
  • UROD: uroporphyrinogen decarboxylase
  • UROS
    Uros

    Uros are a pre-Incan people that live on 42 self-fashioned floating artificial island in Lake Titicaca Puno, Peru and Bolivia. The Uros use the Totora to make boats of bundled dried reeds, and to make the islands themselves....
    : uroporphyrinogen III synthase
    Synthase

    In biochemistry, a synthase is an enzyme which catalyzes a synthesis process.Following the EC number classification, they belong to the group of ligases, with lyases catalysing the reverse reaction....
     (congenital erythropoietic porphyria)


See also

  • bilirubin metabolism
  • chlorin
    Chlorin

    In organic chemistry, a chlorin is a large heterocyclic aromatic ring consisting, at the core, of three pyrroles and one pyrroline coupled through four methine linkages....
  • corrin
    Corrin

    A corrin is a macrocycle related to the porphyrin ring in hemoglobin, consisting of 4 pyrrole subunits, joined on opposite sides by a C-CH3 methylene link, on one side by a C-H methylene link, and with the two of the pyrroles joined directly....
  • cobalamin
    Cobalamin

    Cobalamin may refer to several substances depending on the upper axial ligand of the cobalt ion. These are:*Cyanocobalamin , which is not found in nature....
  • respiration (physiology)
    Respiration (physiology)

    In animal physiology, respiration is the transport of Oxygen from the outside air to the cells within Tissue s and the transport of carbon dioxide in the opposite direction....